AGuIX® from bench to bedside-Transfer of an ultrasmall theranostic gadolinium-based nanoparticle to clinical medicine.

AGuIX® are sub-5 nm nanoparticles made of a polysiloxane matrix and gadolinium chelates. This nanoparticle has been recently accepted in clinical trials in association with radiotherapy. This review will summarize the principal preclinical results that have led to first in man administration. No evidence of toxicity has been observed during regulatory toxicity tests on two animal species (rodents and monkeys). Biodistributions on different animal models have shown passive uptake in tumours due to enhanced permeability and retention effect combined with renal elimination of the nanoparticles after intravenous administration. High radiosensitizing effect has been observed with different types of irradiations in vitro and in vivo on a large number of cancer types (brain, lung, melanoma, head and neck…). The review concludes with the second generation of AGuIX nanoparticles and the first preliminary results on human.

Imaging the Tumor Microenvironment.

The tumor microenvironment consists of tumor, stromal, and immune cells, as well as extracellular milieu. Changes in numbers of these cell types and their environments have an impact on cancer growth and metastasis. Non-invasive imaging of aspects of the tumor microenvironment can provide important information on the aggressiveness of the cancer, whether or not it is metastatic, and can also help to determine early response to treatment. This chapter provides an overview on non-invasive in vivo imaging in humans and mouse models of various cell types and physiological parameters that are unique to the tumor microenvironment. Current clinical imaging and research investigation are in the areas of nuclear imaging (positron emission tomography (PET) and single photon emission computed tomography (SPECT)), magnetic resonance imaging (MRI) and optical (near infrared (NIR) fluorescence) imaging. Aspects of the tumor microenvironment that have been imaged by PET, MRI and/or optical imaging are tumor associated inflammation (primarily macrophages and T cells), hypoxia, pH changes, as well as enzymes and integrins that are highly prevalent in tumors, stroma and immune cells. Many imaging agents and strategies are currently available for cancer patients; however, the investigation of novel avenues for targeting aspects of the tumor microenvironment in pre-clinical models of cancer provides the cancer researcher with a means to monitor changes and evaluate novel treatments that can be translated into the clinic.

Azide Tripodal Dendrons from Behera's Amine and Their Clicked Dendrimers.

Diazo transfer reactions on Behera's amine and its next-generation analogue formed G0 and G1 azide dendrons bearing three and nine tert-butyl-protected esters, respectively. The utility of the new dendrons was demonstrated by copper-catalyzed azide-alkyne cycloaddition, with 1,3,5-triethynylbenzene, forming two novel dendrimers in a convergent manner. Acid-mediated dendrimer deprotection was successful, and the resulting carboxy-terminated dendrimers were analyzed by NMR and DOSY experiments.

Bifunctional chelates optimized for molecular MRI.

Important requirements for exogenous dyes or contrast agents in magnetic resonance imaging (MRI) include an effective concentration of paramagnetic or superparamagnetic ions at the target to be imaged. We report the concise synthesis and characterization of several new enantiopure bifunctional derivatives of (α(1)R,α(4)R,α(7)R,α(10)R)-α(1),α(4),α(7),α(10)-tetramethyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTMA) (and their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) analogues as controls) that can be covalently attached to a contrast agent delivery system using either click or peptide coupling chemistry. Gd complexes of these derivatives can be attached to delivery systems while maintaining optimal water residence time for increased molecular imaging sensitivity. Long chain biotin (LC-biotin) derivatives of the Eu(III) and Gd(III) chelates associated with avidin are used to demonstrate higher efficiencies. Variable-temperature relaxometry, (17)O NMR, and nuclear magnetic resonance dispersion (NMRD) spectroscopy used on the complexes and biotin-avidin adducts measure the influence of water residence time and rotational correlation time on constrained and unconstrained systems. The Gd(III)-DOTMA derivative has a shorter water residence time than the Gd(III)-DOTA derivative. Compared to the constrained Gd(III)-DOTA derivatives, the rotationally constrained Gd(III)-DOTMA derivative has ∼40% higher relaxivity at 37 °C, which could increase its sensitivity as an MRI agent as well as reduce the dose of the targeting agent.

Evolution of iridium-based molecular catalysts during water oxidation with ceric ammonium nitrate.

Organometallic iridium complexes have been reported as water oxidation catalysts (WOCs) in the presence of ceric ammonium nitrate (CAN). One challenge for all WOCs regardless of the metal used is stability. Here we provide evidence for extensive modification of many Ir-based WOCs even after exposure to only 5 or 15 equiv of Ce(IV) (whereas typically 100-10000 equiv are employed during WOC testing). We also show formation of Ir-rich nanoparticles (likely IrO(x)) even in the first 20 min of reaction, associated with a Ce matrix. A combination of UV-vis and NMR spectroscopy, scanning transmission electron microscopy, and powder X-ray diffraction is used. Even simple IrCl(3) is an excellent catalyst. Our results point to the pitfalls of studying Ir WOCs using CAN.

A fluorinated dendrimer-based nanotechnology platform: new contrast agents for high field imaging.

OBJECTIVES: We aimed to develop a directly detected magnetic resonance imaging (MRI) contrast agent for use with high fields based on a nanoscale fluorinated dendrimer-based platform for F MRI and overcome some of the problems with F MRI. MATERIALS AND METHODS: The dendrimers were prepared in a convergent manner by making the appropriate dendron, followed by coupling to a central core. The dendrons were prepared by attaching 3 equivalents of the fluorinated amino acid to the 3 carboxylic acids of the repeat branch unit followed by deprotection of the amine branch point, and either coupling to another repeat branch unit (increasing the generation G) or used directly allowing the precise growth of the dendrimer. The size of the dendrimers was determined by diffusion nuclear magnetic resonance (NMR) spectroscopy. The toxicity of the dendrimers was measured using the MTT assay. Fluorine longitudinal relaxation time measurements were performed on a Bruker ACP-500 NMR using a saturation recovery experiment at 470.59 MHz frequency. Healthy 150 g Sprague-Dawley female rats were imaged using a dendrimer solution. RESULTS: The size of the dendrimers is generally less than 3 nm, 2 orders of magnitude smaller than the size of the perfluorocarbon nanoparticles (about 200 nm). The longitudinal relaxation time, T1, decreases with increasing dendrimer generation. A significant improvement in relaxation rate and signal-to-noise ratio can be achieved by either the chemical modification of the dendrimer with a gadolinium-chelate or by the physical addition of exogenous contrast agent. Although the dendrimers with fluorine in the surface layer are toxic, this toxicity is easily reduced by burying the fluorine further into the dendrimer interior. (19)F MR images of the rat using the dendrimer solution were rapidly obtained at 7 Tesla, the strong contrast in the heart generated by the dendrimer can be seen. CONCLUSIONS: A novel fluorinated dendrimer-based nanotechnology platform in (19)F MRI and a new bifunctional DOTA chelate were prepared and characterized. We introduce 2 methods for reducing the (19)F longitudinal relaxation time: (a) Increasing the generation; (b) covalent and noncovalent introduction of Gd(III)-chelates. A new bifunctional Gd(III)-chelate is presented. The investigations of imaging on rats suggest potential importance of the dendrimers in (19)F MRI application.